Studies on agents with mixed NO-dependent vasodilating and beta-blocking activities.
OBJECTIVE
A series of derivatives having a propranolol-like moiety linked to NO-donor furoxan substructures were synthesized. The main objective of this investigation was to obtain agents with mixed NO-dependent vasodilating and beta-blocking activities.


METHODS
Most of the target compounds were synthesized from the appropriate furoxans bearing XCH2CH2NH2 (X = O, S, SO2) chains at the 4 position of the ring, using Al(C2H5)3 in methylene chloride solution and (+/-)2,3-epoxypropyl 1-naphtyl ether. Two of the final products (X = CONH) were obtained by coupling the appropriate furoxancarboxylic acids with N-[2-hydroxy-3-(1-naphthoxy)propyl]-ethylenediamine. beta 1- and beta 2-blocking activities were examined on isolated guinea pig right atria and on guinea pig trachea respectively. Vasodilating properties were assessed on endothelium denuded strips of rat aorta.


RESULTS
Some derivatives behave as well balanced "hybrids" displaying NO-dependent vasodilating and beta-blocking properties in the same concentration range. Some others display either prevalent beta-blocking or vasodilating activity. Generally speaking hybrid formation lowers the affinity for beta-receptors, in particular for beta 2-type, to give an increase in beta 1/beta 2 selectivity.


CONCLUSIONS
The furoxan system is a flexible tool in designing analogues of propranolol whose NO-donating and beta-blocking properties are modulated over a wide range.
Boschi
D
D
Dipartimento di Scienza e Tecnologia del Farmaco, Torino, Italy.
Di Stilo
A
A
Cena
C
C
Lolli
M
M
Fruttero
R
R
Gasco
A
A
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000737:chemistry; D011433:Propranolol / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects; D014132:Trachea / Q000187:drug effects*; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D010069:Oxadiazoles; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D014665:Vasodilator Agents; D009569:Nitric Oxide; D011433:Propranolol